Dr. Phyllis August's application for a K24 is based on her accomplishments as an investigator in patient oriented research, her significant track record of mentoring young investigators, and the research plan that explores an exciting new area of investigation in hypertension and renal disease in humans. Dr. August's past research has focused on hypertension and renal disease, especially hypertensive disorders in pregnancy. She has made original and significant discoveries with respect to regulation of blood pressure and calcium metabolism in normal and hypertensive pregnancy, and recently discovered that transforming growth factor-beta1 (TGF-beta1) is hyperexpressed in hypertensives. Also, TGF- beta1 was hyperexpressed in Africa Americans with hypertension and/or renal disease compared to their Caucasian counterparts. The research proposed for this award explores the role of TGF-beta1 hyperexpression in the pathogenesis of renal disease and hypertension. The objective of this research is to test the hypothesis that hyperexpression of TGF-beta1, a multifunctional cytokine clearly shown to induce renal disease in experimental models, is a risk factor for the progression of renal disease to end stage renal disease (ESRD) in humans. That TGF-beta1 overexpression is more frequent in African Americans, a population at greater risk for ESRD than Caucasians, and that TGF-beta1 expression is determined by TGF-beta1 DNA polymorphisms will be explored in this study with conceptually interrelated clinical and laboratory studies. Dr. August will have the primary responsibility for these studies in the next 5 years. Studies suitable for beginning investigators to develop research careers are also proposed and include, 1) investigation of TGF-beta1 as a therapeutic target for angiotensin II receptor blockade, 2) characterization of placental cytokine gene expression profiles in normal and hypertensive pregnancy, 3) clinical studies of human renovascular hypertension. Further goals include obtaining additional training in research methodology, biostatistics, and genetic epidemiology. A long-term goal is to further develop the research program in hypertensive disorders of pregnancy by training young investigators. The resources and environment at Cornell including the laboratory expertise of Dr. Suthanthiran, the broad based patient population available via the Hypertension Center and by the applicant's joint appointment in Obstetrics, the established clinical research programs (including GCRC) together provide the necessary environment to conduct the proposed research and provide mentoring to new investigators. The K24 award will provide invaluable protected time for the development of the above research protocols, for obtaining new research skills, and for ensuring the mentoring of new investigators who will continue to conduct patient oriented research in the field of kidney disease, hypertension, and hypertension in pregnancy.